Alcohol consumption is characterized by bouts of moderate drinking that may damage the brain and impair cognition. Abstract thinking, cognitive flexibility and inhibition of competing responses are impaired after binge alcohol consumption. Furthermore, binge drinking has been proposed as a risk factor for the development of dementia. Most studies documenting ethanol-evoked alterations in learning and memory in rodents have employed high doses of ethanol administered over a period of days or repeated bouts of extended ethanol administration followed by periods of withdrawal. In these experiments, blood ethanol concentrations greater than 250 mg/dL are achieved. Although, similar blood levels are detected in heavy drinkers, binge drinkers often exhibit lower blood levels and binge alcohol drinking is defined as alcohol consumption that yields blood alcohol levels of 80 mg/dL or greater within a 2 h drinking period. We, therefore, asked the question as to whether cognitive impairment occurs in rats following exposure to moderate doses of ethanol that produce blood ethanol concentrations similar to those following binge ethanol intoxication in humans. For these studies, rats received ethanol (3.4 g/kg) or an equivalent volume of water once daily by gavage for 6 days. The dose of ethanol and treatment regimen employed produces blood ethanol concentrations (150-190 mg/dl) analogous to those in humans following repeated bouts of moderate dose ethanol consumption. Alterations in spatial learning and memory were analyzed using the Barnes maze. Since clinical studies have shown that cognitive performance improves during the course of abstinence, performance was analyzed at two time points: 3-6 days and 11-14 days after the cessation of ethanol exposure. Spatial learning and memory, as assessed in the Barnes maze, were markedly impaired 3-6 days following the cessation of ethanol treatment. Consistent with recovery of cognitive function in human subjects following protracted abstinence, error rate and escape latency returned to control values at later time points. Reversal learning, however, was impaired throughout the two week observation period. These data demonstrate that bouts of moderate dose ethanol administration are sufficient to promote cognitive inflexibility. It is suggested that impairment of spatial learning, memory and reversal learning in rats, which are thought to result from aberrations in hippocampal/cortical neurotransmission, may model, respectively, transient and long-lasting cognitive impairment in human binge alcohol drinkers. Using the technique of in-vivo microdialysis to quantify neurotransmitter overflow, several investigators have shown that long term exposure to high doses of ethanol increases dialysate concentrations of glutamate in the hippocampus. Questions, however, exist as to whether the observed changes reflect altered glutamate uptake and/or release. Furthermore, it is unclear whether hippocampal glutamate dynamics are altered following short term exposure to a moderate dose ethanol treatment regimen that produces spatial learning and memory deficits. Using conventional and quantitative microdialysis techniques, a series of studies was conducted to quantify glutamate dynamics in the CA3 region of the dorsal hippocampus, a region implicated in spatial working memory (Addiction Biology, in press). Rats received ethanol or water as described above. Microdialysis was conducted two days after the cessation of treatments. Basal and depolarization-induced glutamate overflow were elevated in ethanol-treated animals. In contrast, basal and stimulation-evoked GABA overflow were unaltered. Quantitative no-net-flux microdialysis was used to determine if changes in dialysate glutamate levels following ethanol administration are due to an increase in release and/or a decrease in uptake. To confirm the validity of this method for quantifying basal glutamatedynamics, extracellular concentrations of glutamate and the extraction fraction, which reflects changes in analyte clearance, were quantified in response to retro-dialysis of a glutamate uptake blocker. Perfusion of the uptake blocker significantly decreased the extraction fraction for glutamate resulting in augmented extracellular glutamate concentrations. Repeated ethanol administration did not alter glutamate extraction fraction. However, extracellular glutamate concentrations were significantly elevated, indicating that glutamate release is increased as a consequence of repeated ethanol administration. These data demonstrate that repeated bouts of moderate ethanol consumption alter basal glutamate dynamics in the CA3 region of the dorsal hippocampus. It is hypothesized that dysregulation of glutamate transmission in this region may contribute to deficits in cognitive function associated with moderate dose ethanol use. K-opioid receptors and dynorphin, the endogenous ligand for this opioid receptor type, are enriched in the hippocampus where they modulate glutamate transmission. Both glutamate and dynorphin have been implicated in the modulation of long-term depression, a form of synaptic plasticity which is important for learning. Importantly, however, excess glutamate is toxic to neurons and can impair learning and memory. We have obtained evidence that tissue levels of dynorphin, but not other opioid peptides, are elevated in the hippocampus of human alcoholics. Expression of prodynorphin, the gene encoding dynorphin, is also increased. Given the role of the dynorphin/k-receptor system in synaptic plasticity, we examined whether its up-regulation contributes to cognitive deficits or neurochemical changes produced by alcohol. Rats were treated with alcohol as above. After treatment cessation they received an injection of a selective, long-acting k-opioid receptor antagonist. Our studies have revealed that systemic administration of a selective k- opioid receptor antagonist following repeated, binge alcohol administration prevents memory deficits produced by ethanol. K-opioid receptor antagonist treatment also prevents associated changes in hippocampal glutamate release. Blood alcohol concentrations are unaffected by the antagonists suggesting that a pharmacodynamic mechanism underlies the protective effects of k-opioid receptor antagonism. Alcohol and other drugs of abuse produce marked alterations in the activity of dopamine (DA)neurons comprising the mesocorticolimbic system. This action is thought to contribute to the effects of these agents on incentive motivation and their abuse liability. The growth factor, glial cell line-derived neurotrophic factor (GDNF), is critical for the survival, maintenance, and function of various neuronal populations in the CNS and for the protecting of midbrain DA neurons from neurotoxic damage. Evidence that GDNF factor modulates prodynorphin expression and contributes to alcohol addiction has also been obtained. Collaborative studies with Ron and colleagues(Gallo Institute), have delineated a key role of this growth factor in the regulation of mesocorticolimbic transmission (Journal of Neuroscience, in press). Spontaneous firing of ventral tegmental area dopamine neurons provides ambient levels of DA in the nucleus accumbens and prefrontal cortex. Our studies show that GDNF is produced in the accumbens and retrogradely transported by DA neurons to the accumbens. There, it positively regulates the spontaneous firing of DA neurons by a mechanism that requires mitogen-activated protein kinase activation.We further show that the consequence of GDNF-mediated activation of this signaling cascade is an increase in DA overflow in the accumbens. These results demonstrate that GDNF produced in the nucleus accumbens serves as a retrograde enhancer that upregulates the activity of the mesocorticolimbic DA system.